All FDA-approved peripherally active μ-opioid receptor antagonists f0r opioid-induced constipation (OIC) are safe and effective for pain, researchers found.

Meta-analysis of 27 placebo-controlled trials in more than 5,000 patients with cancer- and non-cancer related pain showed the relative risk (RR) of failure to respond to methylnaltrexone (Relistor), naloxone (Narcan), alvimopan (Entereg), axelopran, naldemedine (Symproic), and naloxegol (Movantik) was 0.69 (95% CI 0.62-0.77), according to Judy W. Nee, MD, of Beth Israel Deaconess Medical Center in Boston, and colleagues.

The number needed to treat was five (95% CI 4.0-7.0), they wrote in Clinical Gastroenterology and Hepatology. “Despite variable medication dosages and significant heterogeneity across studies, all studies showed superiority of these agents compared to placebo,” the authors stated.

The prescription-strength laxatives prucalopride (Resolor) and lubiprostone (Amitiza) were also superior to placebo for resolving OIC, the analysis showed. When these agents were included with the μ-opioid receptor antagonists, the overall RR of failure to respond to therapy was slightly higher at 0.70 (95% C 0.64-0.75) but the overall number of patients needed to treat was still five (95% CI 4.0-7.0).

“While our analysis supports the usage of lubiprostone for OIC compared to placebo, prescription laxatives may not be superior to over-the-counter laxatives,” Nee’s group pointed out.

The meta-analysis includes additional study reports published after the last meta-analysis in 2013. The FDA approved naloxegol and naldemedine for OIC in 2014, the authors noted. “With the addition of newer agents to treat OIC, this shows a slightly higher overall number needed to treat of five compared to the previous meta-analysis.”

Notably, treatment was more likely to be effective in study populations taking higher doses of opiates at baseline and in patients with OIC refractory to laxatives. “Both of these findings suggest that the subset of patients on opioids with more severe constipation respond more favorably to agents targeted mechanistically against μ-opioid receptors,” they said. “On the other hand, OIC criteria and duration of studies did not influence outcome in the treatment of OIC.”

Madhusudan Grover, MD, of the Mayo Clinic in Rochester, Minnesota, told MedPage Today that the findings are important for clinical practice.

Even though these agents are more effective in patients on higher doses of opioids, “they should be considered in patients across the spectrum of opioid doses in conjunction with an opioid de-escalation strategy,” said Grover, who was not involved with the study. The meta-analysis also showed that methylnaltrexone was more efficacious for patients with cancer-related pain than in those with non-cancer related pain, he noted.

Clinicians need to be aware of OIC as a potential complication of opioid use, Grover said. “When laxatives fail, this report shows that OIC can be efficiently treated with readily available, FDA-approved μ-opioid receptor antagonists and secretagogues, such as lubiprostone and prucalopride.”

Although these results are consistent with clinical observations and practice patterns in general, “in clinical practice, one is likely to try laxatives first regardless of the etiology before trying additional agents,” he pointed out. And while the number needed to treat was consistent with results from studies of treatment for functional constipation or irritable bowel syndrome (IBS) with constipation, there may be other patients who get a partial response, Grover said.

The meta-analysis also confirmed the overall safety of μ-opioid receptor antagonists for treating constipation caused by opioids ranging from oxycodone to morphine to methadone. Of the 5,390 patients on active treatment, 58% experienced adverse effects compared with 52% of 3,491 on placebo. Of those taking μ- opioid receptor antagonists, 12.8% had abdominal pain and 11.5% experienced nausea and/or vomiting.

Although the type of opioid shouldn’t influence development of OIC, differences in symptom severity may have been related to frequency and dosage, the authors said. In one study, for instance, 81% of patients who used opioids every day experienced OIC compared with 46% who took them up to three times a week.

Estimates of OIC in patients taking opioids on a chronic basis indicate the prevalence could be as high as 70%. This can have a significant impact on patients’ quality of life and productivity, resulting in significant direct and indirect costs. About one-third of patients discontinue therapy to normalize bowel function and experience increased pain as a result.

Despite FDA approval, there are no formal guidelines for the clinical use of the u-opioid antagonists naloxegol, methylnatrexone, fixed-dosage oxycodone/naloxone, and naldemedine, and these agents are probably underused, the investigators indicated. The study was limited by significant heterogeneity across the 27 studies, they said.